In conversation with Dr. Cyril Zipfel

email protected email protected 1. What initially drew you to the field of plant biology and how did your interest evolve into a focus on plant immunity? To be frank, ending up in plant biology was something that simply happened. Like many kids, I was always interested in nature, but I was torn between art and biology. I chose biology and started university in Strasbourg, France. The first 2 years were tough because they were mostly math, chemistry, and physics. When I finally had the chance to specialize, I initially leaned toward ecology; my grandfather and uncle were forest engineers, so forestry felt like a natural direction. I transferred to the University of Nancy (France) that offered a connection to forestry, and as part of the program, all students were required to do internships. I joined a forestry research institute where a lab was doing molecular biology. I spent the summer there and loved it, especially working with GUS reporter genes, which felt very exciting at the time. After that experience, I decided to leave forestry and pursue a more molecular-focused degree. During my master's in Paris, I joined a plant molecular biology lab in Gif-sur-Yvette working on auxin signaling and had planned to stay for a PhD. But due to personal circumstances, I relocated to Basel in Switzerland, where I began working on plant immunity. It was really a series of events and life decisions that brought me into the field. Even after my PhD, I considered switching to animal immunity. What truly motivates me are signaling pathways; I see them as puzzles in which you assemble pieces to build a coherent picture. 2. Can you share a defining moment or mentor in your early scientific career who significantly influenced your research direction? At each stage of my development, a few people played important roles. It may sound cliché, but it began in high school. I wasn't necessarily the best student, but my biology teacher saw potential in me, pushed me, and motivated me to pursue biology. During my internship at the forestry institute, I worked closely with a PhD student, Frank Ditengou. He made the work extremely enjoyable—we shared enthusiasm for the project, and he gave me the freedom to explore my own ideas. That experience made me switch fields. Later, at the end of my master's, I was working on auxin signaling in tobacco and had secured a fellowship from the French government to stay for a PhD in that lab. But an English postdoc, Jim Bauly, knew I couldn't remain in Paris for personal reasons. One day he brought me an ad for a PhD program at the Friedrich Miescher Institute in Basel and told me, “You should apply. Don't be afraid, you have nothing to lose.” His encouragement is what ultimately led me to Thomas Boller's lab and to working on FLS2 and other receptor kinases thereafter. These were truly defining moments. 3. Your work has spanned several institutions and countries. How have these international experiences shaped your scientific thinking and leadership style? I've essentially been an expat for 25 years. I'm originally from France, but I completed only my early studies there before moving to Switzerland. So, I experienced the French education system and had a brief look at the French research environment before entering the Swiss system. I was incredibly fortunate to be at the Friedrich Miescher Institute in Basel, funded by a pharmaceutical company. The facilities and funding were exceptional, and I often say how lucky I was to have that environment during my PhD. Later, I moved to the UK and again was fortunate to join The Sainsbury Laboratory in Norwich, funded by the Gatsby Charitable Foundation. What stood out there was the culture: they focused entirely on excellence and gave scientists the freedom to pursue whatever questions excited them. This deeply shaped my approach. You should pursue the questions that genuinely excite you; others might not immediately see the value, but it's your job to show them. During my postdoc and then as group leader, I absorbed the Anglo-Saxon mentality of bold recruitment—hiring people for their creativity and ideas rather than for specific projects. Now, I'm in Zurich, back in Switzerland. Joining a large university after working exclusively in research institutes was a big change. At first, I was scared because I had to teach. But teaching helps you to be a better scientist. We tend to become overspecialized, and teaching forces you to return to fundamentals, understand them thoroughly, and communicate them clearly. Interacting with students is incredibly enriching—they ask questions you haven't thought about. And when you manage to excite even a few students, it's very rewarding. 4. You're well known for your work on pattern-recognition receptors like FLS2. Could you briefly explain why these receptors are so crucial in plant immune responses? They are the plant's first sentinels, constantly sensing the environment and detecting potential danger. For many years, they were underappreciated. When you study infection, you study exceptions: cases where adapted pathogens have evolved to suppress this layer of immunity. But most plants around us remain healthy precisely because these receptors are working constantly behind the scenes. Over the past two decades, we've learned that pathogens must either evade recognition or suppress downstream responses to be virulent. If they can't do that, they simply won't infect the plant. That highlights how crucial these receptors are. 5. What have been some of the major technical or conceptual challenges you've faced in dissecting plant innate immune signaling pathways? When we began working on receptors about 20 years ago, they were understudied mainly because they were technically difficult to investigate. They are low-abundance, membrane-localized proteins, making biochemistry extremely challenging. Tools have improved since then, but at the time it was very difficult. Conceptually, understanding signaling specificity was—and is still—a major challenge. How does recognition of a ligand by a receptor lead to specific downstream outputs and not others? Addressing that required identifying downstream components, understanding how signaling is organized, and how it is regulated. These remain active research areas today. 6. How has the discovery of receptor co-receptors like BAK1 reshaped our understanding of signaling specificity in plant immunity? BAK1's role was discovered during my PhD, and I vividly remember the debates at the time, why would another receptor kinase be needed? In animals, receptor tyrosine kinases were already known to form complexes, but in plants this was less obvious. We now know that most leucine-rich repeat receptors require co-receptors like BAK1. It has become a paradigm: most, if not all, ligand-binding receptor kinases in plants require ligand-induced dimerization with a co-receptor for activation. Still, many questions remain. How can BAK1 form complexes with so many different receptors? And how do these complexes produce distinct signaling outputs? 7. There's growing interest in translating findings from arabidopsis to crop plants. What are the key hurdles in applying this knowledge in agricultural contexts? We've always been interested in translational aspects. Many experiments in Arabidopsis are performed under highly controlled conditions, and the results often look very convincing. But many promising findings fail to translate to the field. One reason is that Arabidopsis is not always necessarily representative of many major crops. The bigger challenge is translating controlled-environment findings into the complexity of real fields. Different genotypes behave differently due to domestication and breeding. Fields themselves are heterogeneous—soil properties, nutrients, and microclimates vary even within a single field. And the environment fluctuates constantly across days and seasons. Researchers often reduce variability to make experiments tractable, but that makes field translation difficult. 8. In your view, what have been the most transformative discoveries in plant immunity over the past two decades? A major conceptual advance has been the framework of the immune system being organized into two main perception branches: PTI and ETI. While the distinction can be oversimplified, it has been extremely influential. Equally transformative is recognizing the interconnections between PTI and ETI. Initially seen as separate pathways, they are now understood to be highly interconnected. From the ETI side, the discovery of resistosomes was a major shift. For decades, genetic screens struggled to reveal classical signaling pathways downstream of NLRs. The realization that activated NLRs form supramolecular complexes that directly execute responses fundamentally changed our understanding. Another major discovery is the complex relationship between plant immunity and the microbiome, both in roots and shoots. Understanding how plants tolerate and shape their microbiomes, and how microbiomes influence immunity, is crucial. 9. What emerging technologies or approaches do you believe will most significantly impact plant immunity research in the coming years? AI has already changed how we approach research. It allows us to rapidly generate hypotheses and may hopefully soon enable us to design immune receptors with entirely new recognition specificities—progress is already being made by expanding receptor recognition ranges. But we also need developments in other areas, such as phosphoproteomics. We're seeing improvements in instrumentation and in techniques for enriching specific cell types or isolating plant cells more rapidly using methods like microfluidics. Historically, we've looked at things in a crude way: grinding entire tissues. Now we need to move toward tissue- and cell-level resolution. Transcriptomics has been heading in that direction for over a decade, and similar advances in phosphoproteomics and peptidomics are on the horizon. 10. What pressing challenges does the field of plant immunity still need to address, especially regarding global agriculture and food security? We often publish great papers that end with claims about improving crop protection, but there remains a large gap between discovery and application. A major bottleneck—especially in Europe—is societal acceptance of new plant-breeding technologies. Climate change will only worsen the challenges. Take viruses, for example: we already know powerful solutions using, for example, genome editing or small RNAs. But societal and political resistance often prevents their application. As scientists, we can engage and communicate, but ultimately this is not fully in our hands, which is frustrating. At the same time, regulatory hurdles around pesticides are increasing; they're being banned faster than we can replace them. There is an urgent need for efficient, environmentally friendly alternatives that are safe for humans and animals. 11. Looking back, is there a particular project or discovery you're most proud of? What made it meaningful to you? After almost 20 years running my lab, there are many discoveries I'm proud of. Demonstrating that flagellin perception is relevant for plant immunity was the first. Identifying BAK1 as a major co-receptor and EFR as another important PRR are others. Then there's elucidating how NADPH oxidase is activated by phosphorylation, identifying key phosphorylated residues within receptor complexes, discovering that receptor kinases form nanoclusters in the plasma membrane, and showing that signaling peptides and their receptors are important components of amplification loops, etc. On the more applied side, demonstrating that PRRs can be used to improve disease resistance is also meaningful. It's difficult to pick just one, and doing so feels like I'm overlooking the contributions of the many great people who have worked in my lab. 12. What advice would you offer to early-career researchers entering plant molecular biology today? Find a question that excites you, and make sure the field isn't overcrowded. Follow your passion, stay informed, and understand what others in the field are doing. Build strong networks and be open to collaboration. Science must be collaborative; tackling complex and important questions alone is not feasible.